The propensity of breast cancers to recur following treatment is the most important determinant of clinical outcome, since recurrent breast cancer is typically an incurable disease. Recurrent tumors, in turn, invariably arise from the reservoir of residual neoplastic cells that can persist in patients in a dormant state for many years after treatment of their primary tumor. As such, minimal residual disease, tumor dormancy, and recurrence constitute fundamental manifestations of tumor progression that collectively are responsible for the vast majority of breast cancer deaths. Despite the unrivaled clinical importance of these aspects of breast cancer progression, however, the mechanisms underlying them are largely unknown. Consequently, understanding the biology of residual tumor cells and elucidating the molecular pathways that contribute to tumor dormancy and recurrence is a critical priority in cancer research. To pursue this goal, we have developed and validated a series of doxycycline-inducible transgenic mouse models for MYC, HER2/neu, Wnt1, and Akt-overexpressing breast cancers that display key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. In this application, we will use these models to elucidate the molecular pathways and cellular processes that contribute to tumor dormancy and recurrence. The specific aims of this application are to: 1) Determine the role of uPAR signaling in tumor dormancy and recurrence; and 2) Determine the mechanism of Snail-mediated mammary tumor recurrence. Our observations suggest that each of these pathways promotes the survival and recurrence of dormant residual tumor cells, and the expression of each of these molecules predicts recurrence-free survival in women with breast cancer. Our first aim will test the paired hypotheses that down-regulation of uPAR, ?5?1 integrin, and FAK signaling is required for the establishment of tumor dormancy following down-regulation of the HER2/neu pathway, and that the subsequent up-regulation of uPAR/?5?1 integrin/FAK signaling in dormant tumor cells promotes their re-entry into the cell cycle thereby resulting in tumor recurrence. Our second aim will use orthotopic and intact mouse models to determine the mechanism by which Snail promotes dormant tumor cell survival and mammary tumor recurrence, and the role played by Akt in this process. By probing the biology of residual tumor cells and the pathways that contribute to tumor recurrence, the studies proposed in this application will advance the therapeutic goals of maintaining tumor cells in a dormant state, inducing their death by targeting their survival mechanisms, or blocking preferred pathways of recurrence. We anticipate that this knowledge will facilitate the development of more effective therapeutic approaches to recurrence that could materially alter the treatment options available to millions of breast cancer survivors. PUBLIC HEALTH RELEVANCE: The tendency of breast cancers to recur following treatment is the most important determinant of clinical outcome, since recurrent breast cancer is typically an incurable disease. In this regard, a cardinal feature of human breast cancers is the survival and persistence of residual tumor cells in a dormant state for many years after successful treatment of the primary tumor. Since recurrent breast cancers invariably arise from disseminated tumor cells, understanding their biology and identifying the molecular pathways responsible for recurrence is an essential goal in breast cancer research. Achieving this goal will permit more effective therapeutic approaches to be developed for the millions of breast cancer survivors at risk for recurrence.